Process for preparation of certain 4, 4-disubstituted pyrazolones



3,079,397 PRGCESS EUR PREPARATIQN F CERTAHN 4,4=QESUBSTETUTEDYYRAZGLQNES Fernanda Misani Fiordalisi, es Tarnaqnes Way, Westfieid, NJ.No Drawing. Filed Dec. 29, 1959, er. No. 862,450 2 (Zlaims. ((Il.see-sis Structure I is present in several substituted pyrazolones whichare widely known and used as antipyretic agents. Antipyrine, tolypyrine,aminopyrine, melubrine are some of the most important members of thisseries. All these compounds are characterized by the presence of aphenyl group attached to the nitrogen atom in the l-position and amethyl group in the 3-position. The 4-position is usu ally, but notnecessarily, substituted, because for instance it is unsubstituted inantipyrine and tolyprine. The nitro gen atom in the 2-position issubstituted in antipyrine and melubrine, but it is unsubstituted inaminopyrine.

it seems reasonable to conclude that a phenyl group in the l-positionand a methyl group in the 3-position are essential for antipyreticactivity, but that substitution in the 4-position is not essential.

Several 4,4-dimethyl derivatives, as well as Pyrazole Blue andTartrazine, are derived from Formula II. The existence of structure 111has been invoked to explain the products resulting from methylation withdiazornethane or acylation with acid chlorides and alkali, which areO-alkyl and O-acyl derivatives. Several pyrazolone dyes are derived fromstructure iii.

In spite of the extensive research in the field of pyrazolones, nopharmacological or clinical use has ever been reported for any compoundderived from structure II, more specifically for compounds containingtwo substituents in the 4position. in view of the extensive literaturedata in the field of pyrazolones and the absence of any physiologicalactivity of the known pyrazolones derived from structure II, it wasnovel and surprising to find that compounds derived from structure IIpossess significant value as central depressants and more particularlyas anticonvulsants.

" The object of this invention is to prepare 4,4-disubstitutedpyrazolones, which are unsubstituted on the two nitrogen atoms.

Another object of the invention is to describe the novel method used forthe preparation of the compounds of the invention.

Other objects of the invention will appear from the specification andexamples.

The compounds of the invention have the formula:

3,7,3? Patented Feb. 25, 1%53 in which R is an alkyl group containing upto four carbon atoms, R is an aryl group and R" is selected from thegroup consisting of hydrogen and a low-molecular-weight alkyl group. Itis also possible, according to the invention, that R and R represent thesame substituent.

In view of the essential features indicated above, exhibited bycompounds having antipyretic activity, that is, a phenyl group on thenitrogen in the 1-position and a methyl group in the 3-position, it wasalso novel and unforeseeable that the anticonvulsant activity reachesthe maximum value in 4-methyl-4-phenyl pyrazolone, that is, a compoundwhich is unsubstituted both on the two nitrogen atoms and in the3-position.

The anticonvulsant activity of the compounds of this invention mayperhaps be explained by the fact that they contain the group that is,these compounds are structurally related to known hypnotics and centraldepressants. It is not a mere coincidence that this moiety is found forinstance in hydantoins, disubstituted barbiturates, oxazolidinediones,hexahydropyrimidinediones, Noludar and Doriden.

The fact that the two substituents in the 4-position of the pyrazolonesof this invention are essential to physiological activity is analogousto the barbiturates where S-unsubstituted or S-mOnosubstitutedbarbiturates are well known to be devoid of any physiological activity.Although the mechanism of action of the compounds of the inventionappears to be analogous to the known central depressants, it is to beunderstood that the scope of this invention is not limited bytheoretical consideration of mode of action on the brain centers, mainlybecause such a mode of action is still little known or inadequatelyunderstood.

Anticonvulsant activity is the ability of a compound to preventepileptic seizures, that is, convulsions accom panied by loss ofconsciousness, which are known as grand mal epilepsy, and also theability to control the milder attacks not accompanied by convulsions,known as petit mal.

The method used for the preparation of the compounds of the inventionconsisted of the reaction of an dflxlisdbstituted ester containing acarbonyl group in the ,B-position with hydrazine, as represented below:

According to this equation, R, R and R" have the same meaning asindicated above, that is, R and R may be the same or different and maybe either an alkyl group containing up to four carbon atoms or an arylgroup, and R" may be hydrogen or a low-nolecular-weight alkyl group. Itis also possible that R and R are the same.

The synthesis of the compounds of this invention offered considerablediiliculties. In Karrer Organic Chemistry (Elsevier Publishing Company),4th edition (1950), it is stated on page 798:

A very general synthesis of pyrazolone compounds consists in the actionof hydrazine or hydrazine derivatives on esters of fi-ketonic acids. Ifformyl acetic ester is used in place of the latter, the parentsubstance, the simplest pyrazolone, is formed.

In spite of the statement found inKarrer and in spite of the fact thatthe literature shows many examples of pyrazolone synthesis fromphenylhydrazine and substituted acetoacetic esters, when this basicreaction was applied to the synthesis of the compounds of thisinvention, using hydrazine and disubstituted fi-ketoor p-formyl esters,the reaction was satisfactory only with the lower members. of theseries. For instance, 3,4,4-trimethyl pyrazolone was satisfactorilyprepared from dimethyl acetoacetic ester andhydrazine,'but the reactionfailed when applied to the dibutyl acetoacetic ester. Essentially, thereaction is' an addition of hydrazine to the carbonyl group, complicatedby the basic character of hydrazine, which is a' stronger base thanphenylhydrazine, the lack ofenolization in the ester component becausethe presence of two substitutents in the :x-position' and the relativelyhigher molecular weight of the two s'ubstituents, that is,the butylgroups instead of methyl groups." The lack "of enolization in the estercomponent is responsible for the diificulty in the formation oftheester-hydrazine transition complex; represented 'below by Formula BfMB 'wOQEt Hz The high basicity of hydrazine is expected to make theproton transfer from this transition complex A to the compound shown byB more diflicult than in the corresponding complex, wherephenylhydrazine is involved. Obviously, the equilibrium is not in favorof the hydrazone formation, and for the pyrazolone synthesis whichinvolves a further cyclodehydration step to give'C. The above mentionedtheoretical considerations led to the adoption of the following method.It'was' found that the reaction proceeds satisfactorily by allowingequivalent amounts of'hydrazine and the u disubstituted B-ket'o or fi-formyl ester to react overnight after adjusting the pH to 5, underconditions which provide for the removal of the water formed in thereaction. Thus, decrease of basicity and shifting the equilibrium infavor of the pyraz olone by elimination of the water'formed proved Veryadvantageous.

The reaction may be conveniently carried out by placing molarequivalents of hydrazine and of the ester component, preferably in asolvent,in a flask provided with a Soxlet extraction apparatus andplacing a dehydrating agent in the thimble of the Soxlet extractionapparatus. Calcium oxide and barium oxide are suitable dehydratingagents, but other dehydrating agents, such as magnesium sulfateandcalcium sulfat'e,'may be used. The amount of the dehydrating agentshould be suflicient to absorb all the water formed in the reaction, butan excess is preferable,

Obviously, any technique, which allows for the removal of water, issatisfactory, althoughtthe procedure compris ing refluxing in' a Soxletapparatus with calcium oxide represents the preferred embodiment of theinvention. Ethanol is a suitable solvent, but otherfsolvents inert, tothe reactantsmay be used.

The method has general application for the synthesis of pyrazolonescontaining two relatively high-molecular weight substituents in the 4-positiou and characterized by the absence of substituents on the twonitrogen atoms.

The following examples are given for the purposeo'f illustrating theinvention, but it is to beunderstood that the invention is to be limitedonly by the appended claims.

5..g. ofethyl dibutyl aceto-acetate, 3.4 g. of 85%hydrazine hydrate werediss'olved'in 150 ml; ethanol'and the pH was adjusted to about S bydropwise addition of aceticacid. The solution was refluxed for about 16hours in a flask provided with a Soxlet thimble containing 20 g. ofcalcium oxide. Then thesolution was filtered to remove traces of calciumoxide carried over into the flask, concentrated to about 15 m1. anddiluted with an equal volume of water. A crop of 3 g. of product havinga melting point of 95-100 C. was obtained, which was further purified byrecrystallization from benzene and precipitation with petroleum ether(-B.P. 7090 C.). The melting point of the pure product was 102l03 C.Analysis.Calcd. for C H N O C, 68.53; H, 10.54. Found: C, 68.69; H,10.62.

The substance showed some anticonvulsant activity, but was more toxicthan the 4-phenyl-4-methyl compound described in Example 2.

EXAMPLE 2 4-Methyl-4-Phenyl-5-Pyrazolone Four and three tenths of a gramof ethyl a-formyl ccmethyl phenyl acetate, 3.6 grams of hydrazinehydrate were dissolved in 300 ml. of absolute ethanol, and the solutionwas brought to pH -5 by dro-pwise addition of acetic acid. The solutionwas placed in a flask provided with a Soxlet apparatus, and 40 grams ofcalcium oxide were placed in the thimble. After refluxing for about 17hours, the solution was filtered, concentrated to about 25 ml. anddiluted with an equal volume of water. The crude product, 2.3 grams,recrystallized from heptane and acetone, gave a crop of 1.6 grams ofmelting point98-l01 C.

Extraction with heptane and concentration of the heptane solution raisedthe melting point to 99-101 C. Analysis.--Calcd. for C H N O: N, 16.08.Found: N, 15.87.

4-methyl-4-phenyl pyrazolone was tested by the mini mum electro-shockprocedure. The animals were administered the substance orally, and afterone hour they were subjected to the direct cruren-t stimulus, that is,to about three times the current necessary to produce maxi; mumseizures. The dose required to prevent convulsions in one 'half of theanimals tested, in milligrams per kilogram, that is E13 was 89. Thesubstance had low toxicity, because the NTS that is the amount of drugin milligrams per kilogram, which produced neurological toxic'symptomsin one half of the animals tested, was 187.

l The 3-methyl-4,4-dibutyl pyrazolone, prepared according to Example 1,showed some anticonvulsant activity, but was less active than4-methyl-41phenyl-pyrazolone, and more toxic.

It appears that the absence of the methyl group in position 3 and thepresence of a phenyl group imposition 4 are beneiicial foranticonvulsantactivity.

I claim;

1'. The process of preparing 4,4-disubstituted pyrazq s e o rm lawherein each. of R andR is a member selected-from the groupconsisting ofalkyl of 1 m4 carbonatoms and phenyl, further characterized by the factthat Rmay be thesame as R and R is a member selected from thegroupconsisting of hydrogen and lower alkyl, which comprises the stepsof adjusting to about 5 the pH of an ethanolic solution of a compound offormula RUCOC- (RR )CO-OR wherein R,R and R have the same meaning asabove and R 1 is loweralkyl, and-the equivalent amount of hydrazinehydrate, refluxing said solution in a flask provided with a Soxletthimble, said thimble containing a dehydrating agent which is a memberselected from the group consisting of CaO, BaO, MgSO Na SO and anhydrousK CO continuing refluxing until all the Water formed is removed, andisolating said 4,4 disubstituted pyrazolone from the reaction mixture.

5 6 2. The process according to claim 1, wherein said de- OTHERREFERENCES hydrating agent is Cao in amount exceeding the theorefi'Backer et a1.: Chem. Abstracts, volume 20, page 1990 cal arnountrequired to remove the water formed in the (1926) Beilstein (Handbuch,4m edition), volume 24, 2nd

References Cited in the file of this patent 5 Supplement, page 80(1954).

ST P AbStI'aCtS, volume 49, column 2,637,732 Schmid eta1- May 1953Elderfield: Heterocyclic Compds, volume 5, pages 2,878,263 OIOShIlIkMar. 17, 1959 114 1 9 1957 2,933,391 Feniak et a1 Apr. 19, 1960 10

1. THE PROCESS OF PREPARING 4,4-DISUBSTITUTED PYRAZ OLONES OF FORMULA